Yellow Fever (YF) and Lassa Fever (LF) are two viral hemorrhagic fevers (VHFs) endemic for West and Central Africa. Among causative agents of VHFs, Lassa (LAS) and YF viruses affect the largest number of people in Africa. In endemic areas the "at risk" LAS virus seronegative population may be as high as 59 million, with an annual incidence of illness of 3 million, fatalities up to 67 thousand, and up to 3 million re- infections. The sizeable disease burden and the possibility that LAS virus can be used as an agent of biological warfare make a strong case for vaccine development. There is no vaccine for LF. In contrast, attenuated YF17D, the most successful vaccine developed to date, is widely used to control YF. However, ecological and social changes, ineffective public health policy and insufficient vaccine coverage resulted in a resurgence of YF during last 15 years. Recently the YF17D vaccine has been successfully used as a vector for live vaccines against flaviviruses and as a vaccine vector for flavivirus-unrelated B and T cell epitopes. We use a full-length infectious cDNA clone of the YF17D as a vector of LAS virus genes, GPC and NP, encoding major antigens, glycoproteins and nucleoprotein, respectively. We will test the hypothesis that YF17D/LAS recombinants will effectively express LAS virus major antigens and induce protective immune responses in experimental animals. Strain 13 guinea pigs and rhesus macaques are the best experimental models for LF to comply with the FDA "Two Animal Rule" for development of biodefense vaccines. Our goal is to assess the immunogenicity and efficacy of YF17D/LAS recombinants in a rodent model before pre-clinical trials in non-human primates. Our specific aims are: 1. Generation and validation of recombinant YF17D/LAS viruses;test the hypothesis that the YF/LAS recombinants will be replication-competent and express LAS GP and NP proteins. 2. Test the hypothesis that the vaccine will induce antigen-specific responses against major LAS virus proteins. 3. Efficacy, determine whether YF17D/LAS recombinants will effectively protect strain 13 guinea pigs against LAS virus challenge. Our long-term goal is to develop a live YF17D/LAS bivalent vaccine to control YF and LF in Africa.